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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is only recently that folate deficiency has been implicated in the development of cancer. The mechanisms by which folate might protect against cancer are not clear but may relate to its role in DNA methylation and DNA synthesis. All case-control, cohort and intervention trials reported in English, French, or German, on folate intake or blood levels in relation to the risk of colorectal, breast, and cervix cancer were reviewed. Twenty case-control, and 12 nested case-control or cohort studies were identified. The epidemiological studies consistently show an inverse association between intake and/or levels of folate and the frequency of colorectal carcinomas, and less clearly of adenomas. Long-term use of supplements of folate seems to be of greater benefit than dietary intake. The effect of folate seems to be modulated by alcohol, methionine, and MTHFR polymorphisms. Results from animal studies suggest that folate supplementation might decrease or increase cancer risk depending on dosage and timing. Recent studies also suggest an inverse association between folate intake and breast cancer among women who regularly consume alcohol. Conversely, epidemiological evidence remains uncertain for the role of folate in cervical cancer prevention; the results of two intervention trials on rates of cervical intraepithelial neoplasia regression or progression were negative. An effect of folate later in carcinogenesis is not supported by the few (nested) case-control studies on invasive cervical cancer. Some of the conflicting results may be due to the fact that dietary intake or blood levels of folate do not accurately reflect folate concentrations in the cells of cancer origin. Furthermore, only a few studies have taken into account the modulating effect of alcohol, methionine, and MTHFR polymorphisms in their analyses. The observed inverse associations between folate and risk of cancer, on the other hand, may be confounded by various factors, especially by other potentially protective constituents in fruits and vegetables. Ongoing intervention studies can strengthen evidence for causality by excluding such confounding, but the optimal dose, duration, and stage of carcinogenesis and the appropriate (genetically predisposed) study group for folate chemoprevention are not yet defined.
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PMID:Folate and the risk of colorectal, breast and cervix cancer: the epidemiological evidence. 1175 74

Many epidemiologic, animal and human studies suggest that folate status modulates carcinogenesis. Although these observations have been made in a number of tissues, the data are clearly most compelling for the colorectum. The mechanism(s) by which this modulation is mediated remains ill defined. Alterations in either genome-wide or gene-specific DNA methylation and/or alterations in DNA stability, resulting from DNA strand breaks or uracil misincorporation, are leading candidates in this regard. Folate has a central role in biological methylation and nucleotide synthesis, and therefore it is not surprising that folate depletion has been observed to alter DNA methylation and diminish DNA stability. The hypothesis that these two pathways are the means by which folate modulates cancer risk is also supported by the epidemiological observation that a common polymorphism in the methylenetetrahydrofolate reductase (MTHFR; EC 1.5.1.20) gene differentially affects the relative risk of colon cancer depending on folate status, because MTHFR catalyzes the reaction that determines whether cellular folate is diverted into biological methylation or nucleotide synthesis. This phenomenon suggests that it is an imbalance between biological methylation and nucleotide synthesis that is responsible for folate-related carcinogenesis. The control of cell proliferation, which also is related to DNA methylation, is another candidate mechanism by which folate status modulates carcinogenesis. In cell culture studies, folate supplementation has been observed to suppress excessive cell proliferation. Understanding the mechanisms by which folate status modulates carcinogenesis is important for advancing insight into cancer biology and for facilitating those efforts to translate research in folate and carcinogenesis into effective and safe public health initiatives.
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PMID:Folate status: effects on pathways of colorectal carcinogenesis. 1216 3

Frequent consumption of fresh fruit and vegetables, and polymorphisms in the detoxifying enzyme glutathione S-transferase M1 (GSTM1) and other metabolic genes have been shown to modulate cancer risk at some sites. We have shown recently that DNA adducts, a reliable indicator of genotoxic damage and, possibly, of cancer risk, are modulated by plasma levels of selected micronutrients. Here we further investigate the association between DNA adduct levels and consumption of major food groups and foods, and the estimated dietary intake of nutrients, taking into account the possible modifying effect of metabolic polymorphisms, in a larger sample of 634 healthy adults enrolled in a prospective study in Italy. DNA adducts and five polymorphic metabolic genotypes (GSTM1, GSTT1, NAT2, CYP1A1 and MTHFR) were determined in peripheral leukocytes by using 32P-postlabeling technique and PCR methods. DNA bulky adducts (mean: 7.82 +/- 0.40/10(9) nt) were detected in 482/634 samples (76.0%). Overall, DNA adduct levels were significantly and inversely associated with the intake of raw leafy vegetables (P = 0.02), non-citrus fruits (P = 0.04), potassium (P = 0.01) and beta-carotene (P = 0.05). No association was evident with the five genotypes. Stratification by GSTM1 genotype showed strong inverse associations of DNA adduct levels with increasing consumption of all vegetables combined (P = 0.04), leafy vegetables (P = 0.004), raw leafy vegetables (P = 0.002) and fish (P = 0.03) among 307 GSTM1-null subjects; strong inverse associations also emerged with estimated dietary intakes of beta-carotene (P = 0.004), vitamin E (P = 0.004), niacin (P = 0.02) and potassium (P = 0.01). In contrast, no association emerged among 295 subjects with a GSTM1-wild genotype. Overall, statistically significant interactions in predicting DNA adduct levels were observed between the GSTM1-null genotype and consumption of leafy vegetables (P = 0.01), white meat (P = 0.04), and intake of vitamin C (P = 0.04), vitamin E (P = 0.05) and beta-carotene (P = 0.02). Our results suggest that the role of a diet rich in antioxidants in preventing or reducing DNA adduct formation is restricted to subjects lacking the detoxifying activity of GSTM1 isoenzyme (approximately 50% of the general population).
Carcinogenesis 2004 Apr
PMID:The effects of diet on DNA bulky adduct levels are strongly modified by GSTM1 genotype: a study on 634 subjects. 1465 45

Methionine synthase [5-methyltetrahydrofolate-homocysteine S-methyltransferase (MTR)] is involved in folate-mediated one-carbon metabolism, a pathway known to play a role in colorectal carcinogenesis. We investigated whether the MTR D919G polymorphism was associated with risk of colorectal adenoma in a colonoscopy-based study of 513 cases and 609 controls from Minneapolis, MN. Adenoma risk appeared nonsignificantly increased among women with DG or GG genotype [adjusted odds ratio (OR) versus DD, 1.4; 95% confidence interval (CI), 0.9-2.1] but not men (OR, 1.0; 95% CI, 0.7-1.5). An interaction with methionine intake was observed among women, such that low versus high intake was associated with a 2.3-fold increased risk only among those with DG or GG genotype (95% CI, 1.1-4.9; P for interaction = 0.05). Similarly, risk associated with alcohol intake was not elevated among women with the DD genotype; however, consumption of >7 g of alcohol/day versus none was associated with an increased risk among women with DG or GG genotype (adjusted OR, 2.5; 95% CI, 1.4-4.4; P for interaction = 0.03). An interaction between MTR D919G and the thymidylate synthase (TS or TYMS) 3'-untranslated region polymorphism 1494del6 was also observed among women (P for interaction = 0.007). No evidence of interaction with intake of folate, vitamin B(12), or vitamin B(6) or with genotype at MTHFR C677T or the TS enhancer region 28-bp repeat polymorphism was seen. These findings add to what is known about the complexities of genetic variations in one-carbon-metabolizing enzymes in relation to colorectal carcinogenesis.
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PMID:Methionine synthase D919G polymorphism, folate metabolism, and colorectal adenoma risk. 1474 49

Thymidylate synthase (TS), a key one-carbon metabolizing gene, encodes an enzyme that converts dUMP to dTMP, the rate-limiting nucleotide in DNA synthesis. We recently reported that a promoter polymorphism in TS modified the risk of colorectal cancer as well as the survival rate after the disease. To explore whether TS may play an important role in colorectal carcinogenesis early in the multistaged pathogenic pathway, we investigated the relation between the TS promoter polymorphism and risk of colorectal adenoma in a nested case-control study within the prospective Health Professionals Follow-up Study. We ascertained the TS genotype from 373 incident colorectal adenoma cases and 720 control subjects. Although there was no overall association between the TS promoter polymorphism and adenoma risk, we observed a significant TS-alcohol interaction (P for interaction = 0.009); relative to low alcohol consumers with the 2R/2R genotype, those with high alcohol consumption (>30 g/d) were not at elevated risk if they had the 2R/2R genotype [relative risk (RR), 0.80; 95% confidence interval (95% CI), 0.34-1.90], but were at higher risk if they had the 2R/3R genotype (RR, 1.70; 95% CI, 0.87-3.31), and at the highest risk (RR, 3.16; 95% CI, 1.50-6.63) if they had the 3R/3R genotype. In addition, a significant interaction was observed between the TS promoter polymorphism and the 677C > T polymorphism of methylenetetrahydrofolate reductase (MTHFR; P for interaction = 0.007). These findings lend additional support that one-carbon metabolism is an important process in pathogenesis of colorectal cancer.
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PMID:Polymorphism in the thymidylate synthase promoter enhancer region and risk of colorectal adenomas. 1559 87

Folate takes part in two biological pathways involved in DNA methylation and synthesis, and a potential protective influence of this nutrient chemical against carcinogenicity has been recognized in several sites, including the esophagus. Therefore, the functional polymorphisms in genes encoding folate metabolizing enzymes, MTHFR C677T and MTR A2756G, might be suspected of impacting on esophageal cancer risk. We therefore conducted a matched case-control study of 165 esophageal cancer cases and 495 non-cancer controls to clarify associations among folate intake, MTHFR C677T and MTR A2756G polymorphisms, and esophageal cancer risk. Gene-environment interactions between the two polymorphisms, and drinking and smoking were also evaluated. Folate consumption and MTHFR 677TT were associated with a non-significant tendency for decreased risk while the MTR genotypes did not show any links in themselves; further, when analysis was limited to heavy drinkers, the MTHFR TT genotype significantly decreased esophageal cancer risk [odds ratio (OR) = 0.27, 95% confidence interval (CI), 0.09-0.76]. The OR for the gene-environment interaction between heavy drinking and the 677TT genotype in the case-only design was 0.31 (95% CI, 0.10-0.94), indicating risk with heavy drinking to be 69% decreased in individuals harboring the 677TT genotype. We failed to find any significant interaction between either of the polymorphisms and smoking.
Carcinogenesis 2005 Jul
PMID:Gene-environment interactions between alcohol drinking and the MTHFR C677T polymorphism impact on esophageal cancer risk: results of a case-control study in Japan. 1579 May 87

One-carbon metabolism, in which folate plays an essential role, is involved in DNA methylation and synthesis, and is suspected of impacting on colorectal carcinogenesis. Alcohol is well recognized as a risk factor for colorectal cancer (CRC) and interactions with one-carbon metabolism have also been suggested. Therefore, functional polymorphisms in genes encoding members of this pathway, MTHFR C677T and A1298C (genes for methylenetetrahydrofolate reductase), MTR A2756G (gene for methionine synthase) and TS (gene for thymidylate synthase) tandem repeats polymorphisms, have attracted attention. We conducted a matched case-control study with 257 incident CRC cases and 771 non-cancer controls at the Aichi Cancer Center to clarify associations among folate intake and four polymorphisms with reference to CRC risk. Gene-environment interaction between polymorphisms, drinking and folate consumption was also evaluated. None of the polymorphisms showed any significant impact on CRC risk by genotype alone, but when combined with alcohol consumption the MTHFR 677CC type showed a significantly reduced risk (odds ratio (OR) = 0.45, 95% confidence interval (CI): 0.23-0.86) (P = 0.01). MTR GG showed increased risk only among drinkers (OR = 3.35, 1.40-8.05) (P = 0.047). TS polymorphism did not show statistical significance by genotype alone, while interaction with drinking was significant (P = 0.028). The association was not changed even after stratification by daily folate consumption and drinking habit. In conclusion, we found consistently significant interactions between one-carbon metabolism-related polymorphisms and alcohol drinking.
Carcinogenesis 2005 Dec
PMID:One-carbon metabolism related gene polymorphisms interact with alcohol drinking to influence the risk of colorectal cancer in Japan. 1605 37

Methylenetetrahydrofolate reductase is a key enzyme in folate metabolism, which affects DNA synthesis and methylation and is possibly linked to colorectal carcinogenesis. Alcohol and acetaldehyde have an adverse effect on folate metabolism. This study investigated the relationship of functional MTHFR C677T and ALDH2 polymorphisms to colorectal adenomas with reference to alcohol consumption in a case-control study of male officials in the Self-Defense Forces (SDF) who received a preretirement health examination at two SDF hospitals. The study subjects were 452 cases of colorectal adenoma and 1050 controls with no polyp who underwent total colonoscopy. Genotypes were determined by the PCR-RFLP method using genomic DNA extracted from the buffy coat. Statistical adjustment was made for age, hospital, rank in the SDF, body mass index, cigarette-years and alcohol intake. Neither MTHFR C677T nor ALDH2 showed a measurable association with colorectal adenoma. While high alcohol consumption was associated with a moderately increased risk of colorectal adenoma, neither of the two polymorphisms showed a significant effect on the association between alcohol and colorectal adenoma. Individuals with the variant alleles ALDH2*2 and MTHFR 677T had a decreased risk of colorectal adenomas, showing adjusted odds ratios of 0.70 (95% confidence interval 0.49-1.00) for all adenomas and 0.57 (0.34-0.95) for large adenomas (> or = 5 mm), as compared to individuals with ALDH2*1/1 and MTHFR 677CC genotypes combined. The findings may be interpreted as suggesting that folate inhibits the growth of colorectal adenomas, but further confirmation is needed.
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PMID:Genetic polymorphisms of methylenetetrahydrofolate reductase and aldehyde dehydrogenase 2, alcohol use and risk of colorectal adenomas: Self-Defense Forces Health Study. 1610 33

We conducted a case-control study to investigate the association of nutrient intake involved in the one-carbon pathway of folate for DNA methylation and DNA synthesis and the related enzyme genetic polymorphisms with colorectal cancer. Cases were 107 patients newly diagnosed with colorectal cancer. Controls were 224 subjects matched with cases by sex, age, and residential area. Nutrient intake was assessed by a self-administered, semiquantitative food-frequency questionnaire. Four genetic polymorphisms-MTHFR C677T and A1298C, MTRR A66G, and ALDH2 Glu487Lys-were determined using blood samples. Odds ratios were calculated using conditional logistic regression analysis adjusted for smoking, alcohol consumption, body mass index, and dietary fiber intake. Although folate intake was inversely associated with colorectal cancer, this association was attenuated after further controlling for dietary fiber intake. Neither vitamin B6, vitamin B12, nor vitamin B2, nor any genetic polymorphism was significantly associated with colorectal cancer. MTRR polymorphism interacted with the association of folate (P for interaction = 0.04) or vitamin (P for interaction = 0.02) with colorectal cancer, although the other polymorphisms did not interact with any nutrient intake. In conclusion, the study did not support the existing hypothesis of gene-nutrient interaction in colorectal carcinogenesis.
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PMID:Folate, vitamin B6, vitamin B12, and vitamin B2 intake, genetic polymorphisms of related enzymes, and risk of colorectal cancer in a hospital-based case-control study in Japan. 1635 5

It is becoming increasingly evident that single-locus effects cannot explain complex multifactorial human diseases like cancer. We applied the multi-factor dimensionality reduction (MDR) method to a large cohort study on gene-environment and gene-gene interactions. The study (case-control nested in the EPIC cohort) was established to investigate molecular changes and genetic susceptibility in relation to air pollution and environmental tobacco smoke (ETS) in non-smokers. We have analyzed 757 controls and 409 cases with bladder cancer (n=124), lung cancer (n=116) and myeloid leukemia (n=169). Thirty-six gene variants (DNA repair and metabolic genes) and three environmental exposure variables (measures of air pollution and ETS at home and at work) were analyzed. Interactions were assessed by prediction error percentage and cross-validation consistency (CVC) frequency. For lung cancer, the best model was given by a significant gene-environment association between the base excision repair (BER) XRCC1-Arg399Gln polymorphism, the double-strand break repair (DSBR) BRCA2-Asn372His polymorphism and the exposure variable 'distance from heavy traffic road', an indirect and robust indicator of air pollution (mean prediction error of 26%, P<0.001, mean CVC of 6.60, P=0.02). For bladder cancer, we found a significant 4-loci association between the BER APE1-Asp148Glu polymorphism, the DSBR RAD52-3'-untranslated region (3'-UTR) polymorphism and the metabolic gene polymorphisms COMT-Val158Met and MTHFR-677C>T (mean prediction error of 22%, P<0.001, mean CVC consistency of 7.40, P<0.037). For leukemia, a 3-loci model including RAD52-2259C>T, MnSOD-Ala9Val and CYP1A1-Ile462Val had a minimum prediction error of 31% (P<0.001) and a maximum CVC of 4.40 (P=0.086). The MDR method seems promising, because it provides a limited number of statistically stable interactions; however, the biological interpretation remains to be understood.
Carcinogenesis 2007 Feb
PMID:Multi-factor dimensionality reduction applied to a large prospective investigation on gene-gene and gene-environment interactions. 1695 9


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